What we do
Our Group uses molecular genetic technology to improve the diagnosis and treatment of children with cancer. In particular, we aim to identify cancer-associated genes that are critical for the growth and survival of cancer cells, and then develop pharmaceutical agents that can selectively target them.
We have identified several small-molecule inhibitors of these targets in infants with leukaemia, and in children with high-risk neuroblastoma. Both these groups have particularly poor survival rates compared with children with other tumour types.
Developing inhibitors of defined molecular targets—such as the MLL (Mixed Lineage Leukaemia) oncoprotein and MYCN-associated proteins—provides the opportunity to devise therapies that are more specific in their action, are effective at low concentrations, and have an irreversible effect on cancer cells. We focus on developing clinically relevant small molecules that specifically inhibit leukaemia cells with an abnormal MLL gene, as well as on characterising novel genes and co-factors involved in MYCN-driven neuroblastoma.
Neuroblastoma tumour-associated genes
Contact: Prof Murray Norris AM, firstname.lastname@example.org; Dr Jayne Murray, JMurray@ccia.org.au; Dr Firoozeh Salehzadeh, FSalehzadeh@ccia.org.au; Dr Cheng Xue, CXue@ccia.org.au; Dr Ruby Pandher, RPandher@ccia.org.au
Many children with neuroblastoma present with widely disseminated disease at diagnosis and the prognosis in these cases is dismal. Several prognostic markers have been identified for this disease and one of the most powerful is MYCN oncogene amplification, demonstrated in 25–30% of primary untreated neuroblastomas. We have sought to identify pathways downstream of MYCN that are required for neuroblastoma initiation and maintenance, as these represent potential candidates for therapeutic intervention.
We have undertaken a large ENU-mutagenesis screen using N-ethyl-N-nitrosourea (ENU), a compound that causes heritable mutations in DNA. As a result of this screen, we generated a founder line showing Mendelian inheritance of a specific mutation that prevented neuroblastoma formation. A combination of gene mapping and next-generation sequencing was used to identify the gene, which had a loss-of-function mutation. Although this gene has never previously been shown to have a role in neuroblastoma, our research shows that it has a critical role in the initiation and development of this disease. These studies have the potential to elucidate an entirely novel approach to the treatment and, ultimately, prevention of this refractory childhood malignancy.
Molecular-targeted therapy for infant leukaemia
Leukaemia accounts for the second greatest number of deaths from childhood cancer, after brain cancer. Particularly poor survival rates are found in infants whose leukaemias commonly display abnormalities of the MLL gene (MLLr leukaemia) and are highly resistant to currently applied chemotherapeutic treatment protocols.
We have established a pipeline for the development and characterisation of novel agents for MLLr leukaemia, including high-throughput screening, cellular and molecular characterisation in a large and diverse panel of leukaemia cell lines, in vivo testing in paediatric leukaemia patient-derived xenograft (PDX) models, and efficacy testing of potential new drugs in combination with the leukaemia drugs currently in use.
Several projects are ongoing, reflecting the various approaches taken. These include:
- Re-purposing drugs for MLLr and other high-risk leukaemia therapy, using a chemical library of bioactive molecules.
- Targeting the DNA structure in childhood acute lymphoblastic leukaemia (ALL) using CBL0137, a quinacrine-related DNA-binding compound that acts by targeting FACT (Facilitates Chromatin Transcription).
- Blocking production of NAD (nicotinamide adenine dinucleotide) using the small molecule compound OT-82, an exciting new anti-cancer drug extremely potent in PDX models of MLLr ALL and other high-risk ALL.
- Depleting polyamines from MLLr leukaemia cells through simultaneously blocking polyamine uptake by DFMO and inhibiting uptake from polyamines by AMXT1501.
- Resensitising MLLr ALL towards conventional drugs by targeting proteins of the prosurvival BCL-2 family (BCL-2, MCL1).
Inhibition of MYCN transcription
High levels of the MYCN oncogene in neuroblastoma confer a particularly poor patient prognosis. Using chemical library screening, we have discovered a novel Myc inhibitor (M606) that dramatically reduces MYCN protein expression in human MYCN-amplified neuroblastoma cells, as well as c-myc expression in myc-overexpressing tumour cells. M606 is structurally related to a family of prolyl hydroxylase inhibitors, and like these inhibitors induces HIF1a expression, although this effect is independent of its effects on MYC proteins. This small molecule also has iron chelating activity and its inhibition of MYCN and c-myc is reversible by addition of iron. M606 represents a novel molecule for targeting the MYCN oncogene in neuroblastoma.
Arginine depletion therapy
Contacts: Prof Murray Norris AM, email@example.com; Dr Ruby Pandher, RPandher@ccia.org.au
Arginine is a semi-essential amino acid that is metabolised into ornithine and urea by the expression of cytoplasmic arginase 1 (ARG1) and mitochondrial arginase 2 (ARG2). Neuroblastoma cells have high levels of arginase activity and high ARG2 expression in primary neuroblastomas correlates with worse overall survival. Our research indicates that neuroblastomas have a high metabolic requirement for arginine, therefore making this disease an excellent target for arginine depletion therapy. In addition, we have recently shown that pegylated arginase (BCT-100) administered to Th-MYCN mice can significantly delay tumour development and prolong survival of neuroblastoma-prone Th-MYCN mice. BCT-100 combined with chemotherapy is a potentially exciting new approach for treating patients with high-risk neuroblastoma.
Dr Michelle Henderson
Dr Klaartje Somers
Dr Chengyuan Xue
Dr Ruby Pandher
Dr Jayne Murray
Dr Firoozeh Salehzadeh
Dr Mawar Karsa
Dr Jayne Murray
Senior Research Assistant
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